The urokinase receptor and the regulation of cell proliferation

Roberta Mazzieri; Francesco Blasi

doi:10.1160/TH05-01-0021

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(04): 641-646
DOI: 10.1160/TH05-01-0021

Theme Issue Article

Schattauer GmbH

The urokinase receptor and the regulation of cell proliferation

Roberta Mazzieri

¹Universita’ Vita-Salute San Raffaele and IFOM (FIRC Institute of Molecular Oncology), Milan, Italy

,

Francesco Blasi

¹Universita’ Vita-Salute San Raffaele and IFOM (FIRC Institute of Molecular Oncology), Milan, Italy

› Institutsangaben

Abstract

Summary

The urokinase receptor is a multifunctional receptor modulating both proteolytic dependent and independent processes. It binds the extracellular proteolytic enzyme urokinase and engages lateral interactions with several transmembrane receptors, including integrins and the EGFR. Both, by initiating a proteolytic cascade acting on the extracellular matrix components, and by regulating the activity of important signal transducers, uPAR participates not only in the modulation of cell-cell and cell-extracellular matrix interactions, but also in the control of extracellular signals determining the proliferative state of a cell. Alteration of such a complex and finely modulated mechanism results in unregulated cell proliferation and altered tissue organization, typically associated with tumor progression.

Keywords

Urokinase receptor - proliferation - tumors - metastasis

Volltext

Referenzen

References
1 Vassalli J-D, Baccino D, Belin D. A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J Cell Biol 1985; 100: 8-92.
2 Stoppelli MP, Corti A, Soffientini A. et al. Differentiation- enhanced binding of the amino terminal fragment of human urokinase plasminogen activator to a specific receptor on U937 monocytes. Proc Natl Acad Sci U S A 1985; 82: 4939-43.
3 Ploug M, Rønne E, Behrendt N. et al. Cellular receptor for urokinase plasminogen activator. Carboxylterminal processing and membrane anchoring by glycosyl- phosphatidylinositol. J Biol Chem 1991; 266: 1926-33.
4 Ploug M. Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr Pharm Des 2003; 9: 1499-528
5 Ploug M. Identification of specific sites involved in ligand binding by photoaffinity labeling of the receptor for the urokinase-type plasminogen activator. Residues located at equivalent positions in uPAR domains I and III participate in the assembly of a composite ligandbinding site. Biochemistry 1998; 37: 16494-505.
6 Høyer-Hansen G, Rønne E, Solberg H. et al. Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem 1992; 267: 18224-9.
7 Ragno P, Montuori N, Covelli B. et al. Differential expression of a truncated form of the urokinase-type plasminogen-activator receptor in normal and tumor thyroid cells. Cancer Res 1998; 58: 1315-9.
8 Andolfo A, English WR, Resnati M. et al. Metalloproteases cleave the urokinase-type plasminogen activator receptor in the D1-D2 linker region and expose epitopes not present in the intact soluble receptor. Thromb Haemost 2002; 88: 298-306.
9 Sidenius N, Sier CF, Blasi F. Shedding and cleavage of the urokinase receptor (uPAR): identification and characterisation of uPAR fragments in vitro and in vivo. FEBS Lett 2000; 475: 52-6.
10 Koolwijk P, Sidenius N, Peters E. et al. Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices. Blood 2001; 97: 3123-31.
11 Beaufort N, Leduc D, Rousselle JC. et al. Plasmin cleaves the juxtamembrane domain and releases truncated species of the urokinase receptor (CD87) from human bronchial epithelial cells. FEBS Lett 2004; 574: 89-94.
12 Resnati M, Guttinger M, Valcamonica S. et al. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J 1996; 15: 1572-82.
13 Resnati M, Pallavicini I, Wang JM. et al. The fibrinolytic receptor for urokinase activates the G proteincoupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci U S A 2002; 99: 1359-64.
14 Fazioli F, Resnati M, Sidenius N. et al. A urokinasesensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 1997; 16: 7279-86.
15 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3: 932-43.
16 Kjøller L. The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility. Biol Chem 2002; 383: 5-19.
17 Plesner T, Ralfkiaer E, Wittrup M. et al. Expression of the receptor for urokinase-type plasminogen activator in normal and neoplastic blood cells and hematopoietic tissue. Am J Clin Pathol 1994; 102: 835-41.
18 Lanza F, Castoldi GL, Castagnari B. et al. Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells. Br J Haematol 1998; 103: 110-23.
19 Mustjoki S, Alitalo R, Stephens RW. et al. Blast cell-surface and plasma soluble urokinase receptor in acute leukemia patients: relationship to classification and response to therapy. Thromb Haemost 1999; 81: 705-10.
20 Mustjoki S, Alitalo R, Stephens RW. et al. Plasminogen activation in human leukemia and in normal hematopoietic cells. APMIS 1999; 107: 144-9.
21 Carriero MV, Del Vecchio S, Franco P. et al. Vitronectin binding to urokinase receptor in human breast cancer. Clin Cancer Res 1997; 3: 1299-308.
22 Morita S, Sato A, Hayakawa H. et al. Cancer cells overexpress mRNA of urokinase-type plasminogen activator, its receptor and inhibitors in human non-smallcell lung cancer tissue: analysis by Northern blotting and in situ hybridization. Int J Cancer 1998; 78: 286-92.
23 Pyke C, Kristensen P, Ralfkiaer E. et al. Urokinasetype plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas. Am J Pathol 1991; 138: 1059-67.
24 De Petro G, Tavian D, Copeta A. et al. Expression of urokinase-type plasminogen activator (u-PA), u-PA receptor, and tissue-type PA messenger RNAs in human hepatocellular carcinoma. Cancer Res 1998; 58: 2234-9.
25 Shetty S, Idell S. A urokinase receptor mRNA binding protein-mRNA interaction regulates receptor expression and function in human pleural mesothelioma cells. Arch Biochem Biophys 1998; 356: 265-79.
26 Taniguchi T, Kakkar AK, Tuddenham EG. et al. Enhanced expression of urokinase receptor induced through the tissue factor-factor VIIa pathway in human pancreatic cancer. Cancer Res 1998; 58: 4461-7.
27 Yamamoto M, Sawaya R, Mohanam S. et al. Expression and localization of urokinase-type plasminogen activator receptor in human gliomas. Cancer Res 1994; 54: 5016-20.
28 Sidenius N, Blasi F. The urokinase plasminogen activator system in cancer: recent advances and implication for prognosis and therapy. Cancer Metastasis Rev 2003; 22: 205-22.
29 Pepper MS. Role of the matrix metalloproteinase and plasminogen activator-plasmin systems in angiogenesis. Arterioscler Thromb Vasc Biol 2001; 21: 1104-17.
30 Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000; 407: 249-57.
31 Jain RK, Carmeliet PF. Vessels of death or life. Sci Am 2001; 285: 38-45.
32 Serrano M, Lee H, Chin L. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 1996; 85: 27-37.
33 Lund AH, Turner G, Trubetskoy A. et al. Genomewide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nat Genet 2002; 32: 160-5.
34 Stephens RW, Nielsen HJ, Christensen IJ. et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 1999; 91: 869-74.
35 Heiss MM, Allgayer H, Gruetzner KU. et al. Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med 1995; 1: 1035-9.
36 Allgayer H, Heiss MM, Riesenberg R. et al. Urokinase plasminogen activator receptor (uPA-R): one potential characteristic of metastatic phenotypes in minimal residual tumor disease. Cancer Res 1997; 57: 1394-9.
37 Crowley CW, Cohen RL, Lucas BK. et al. Prevention of metastasis by inhibition of the urokinase receptor. Proc Natl Acad Sci U S A 1993; 90: 5021-5.
38 Min HY, Doyle LV, Vitt CR. et al. Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice. Cancer Res 1996; 56: 2428-33.
39 Lakka SS, Rajagopal R, Rajan MK. et al. Adenovirus- mediated antisense urokinase-type plasminogen activator receptor gene transfer reduces tumor cell invasion and metastasis in non-small cell lung cancer cell lines. Clin Cancer Res 2001; 7: 1087-93.
40 Ploug M, Ostergaard S, Gardsvoll H. et al. Peptidederived antagonists of the urokinase receptor. affinity maturation by combinatorial chemistry, identification of functional epitopes, and inhibitory effect on cancer cell intravasation. Biochemistry 2001; 40: 12157-68.
41 Aumailley M, Gayraud B. Structure and biological activity of the extracellular matrix. J Mol Med 1998; 76: 253-65.
42 Ramirez F, Rifkin DB. Cell signaling events: a view from the matrix. Matrix Biol 2003; 22: 101-7.
43 Vu TH, Werb Z. Matrix metalloproteinases effectors of development and normal physiology. Genes Dev 2000; 14: 2123-33.
44 Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000; 14: 163-76.
45 Lyons RM, Keski-Oja J, Moses HL. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol 1988; 106: 1659-65.
46 Whitelock JM, Murdoch AD, Iozzo RV. et al. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem 1996; 271: 10079-86.
47 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001; 17: 463-516.
48 Naldini L, Tamagnone L, Vigna E. et al. Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J 1992; 11: 4825-33.
49 Naldini L, Vigna E, Bardelli A. et al. Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. J Biol Chem 1995; 270: 603-11.
50 Mars WM, Zarnegar R, Michalopoulos GK. Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA. Am J Pathol 1993; 143: 949-58.
51 Sato Y, Tsuboi R, Lyons RM. et al. Characterization of the activation of latent TGF-β by co-cultures of endothelial cells and pericytes or smooth muscle cells: a self-regulating system. J Cell Biol 1990; 111: 757-63.
52 Nunes I, Shapiro RL, Rifkin DB. Characterization of latent TGF-beta activation by murine peritoneal macrophages. J Immunol 1995; 155: 1450-9.
53 Odekon LE, Blasi F, Rifkin DB. Requirement for receptor-bound urokinase in plasmin-dependent cellular conversion of latent TGF-beta to TGF-beta. J Cell Physiol 1994; 158: 398-407.
54 Shim KS, Kim KH, Han WS. et al. Elevated serum levels of transforming growth factor- 1 in patients with colorectal carcinoma: its association with tumor progression and its significant decrease after curative surgical resection. Cancer 1999; 85: 554-61.
55 Cui W, Fowlis DJ, Bryson S. et al. TGF-ß1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 1996; 86: 531-42.
56 Comoglio PM, Tamagnone L, Boccaccio C. Plasminogen- related growth factor and semaphorin receptors: a gene superfamily controlling invasive growth. Exp Cell Res 1999; 253: 88-99
57 Powell EM, Mars WM, Levitt P. Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon. Neuron 2001; 30: 79-89.
58 Powell EM, Campbell DB, Stanwood GD. et al. Genetic disruption of cortical interneuron development causes region- and GABA cell type-specific deficits, epilepsy, and behavioral dysfunction. J Neurosci 2003; 23: 622-31.
59 Maulik G, Madhiwala P, Brooks S. et al. Activated c-Met signals through PI3K with dramatic effects on cytoskeletal functions in small cell lung cancer. J Cell Mol Med 2002; 6: 539-53.
60 Zhou HM, Nichols A, Meda P. et al. Urokinase-type plasminogen activator and its receptor synergize to promote pathogenic proteolysis. EMBO J 2000; 19: 4817-26.
61 Bolon I, Zhou HM, Charron Y. et al. Plasminogen mediates the pathological effects of urokinase-type plasminogen activator overexpression. Am J Pathol 2004; 164: 2299-304.
62 Fusenig NE, Amer SM, Boukamp P. et al. Characteristics of chemically transformed mouse epidermal cells in vitro and in vivo. Bull Cancer 1978; 65: 271-9.
63 Skobe M, Rockwell P, Goldstein N. et al. Halting angiogenesis suppresses carcinoma cell invasion. Nat Med 1997; 3: 1222-7.
64 Bajou K, Noel A, Gerard RD. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4: 923-8.
65 Bajou K, Masson V, Gerard RD. et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 2001; 152: 777-84.
66 Appella E, Robinson EA, Ullrich SJ. et al. The receptor- binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 1987; 262: 4437-40.
67 Rabbani SA, Desjardins J, Bell AW. et al. An aminoterminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells. Biochem Biophys Res Commun 1990; 173: 1058-64.
68 Rabbani SA, Mazar AP, Bernier SM. et al. Structural requirements for the growth factor activity of the amino-terminal domain of urokinase. J Biol Chem 1992; 267: 14151-6.
69 Rabbani SA, Gladu J, Mazar AP. et al. Induction in human osteoblastic cells (SaOS2) of the early response genes fos, jun, and myc by the amino terminal fragment (ATF) of urokinase. J Cell Physiol 1997; 172: 137-45.
70 Ossowski L, Aguirre-Ghiso JA. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol 2000; 12: 613-20.
71 Aguirre-Ghiso JA, Estrada Y, Liu D. et al. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 2003; 63: 1684-95.
72 Hoshino R, Chatani Y, Yamori T. et al. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 1999; 18: 813-22.
73 Chen G, Hitomi M, Han J. et al. The p38 pathway provides negative feedback for Ras proliferative signaling. J Biol Chem 2000; 275: 38973-80.
74 Liu D, Aguirre Ghiso J, Estrada Y. et al. EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 2002; 1: 445-57.
75 Aguirre-Ghiso JA, Liu D, Mignatti A. et al. Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Mol Biol Cell 2001; 12: 863-79.
76 Lengyel E, Stepp E, Gum R. et al. Involvement of a mitogen-activated protein kinase signaling pathway in the regulation of urokinase promoter activity by c-Haras. J Biol Chem 1995; 270: 23007-12.
77 Lengyel E, Wang H, Stepp E. et al. Requirement of an upstream AP-1 motif for the constitutive and phorbol ester-inducible expression of the urokinase-type plasminogen activator receptor gene. J Biol Chem 1996; 271: 23176-84.
78 Lengyel E, Wang H, Gum R. et al. Elevated urokinase- type plasminogen activator receptor expression in a colon cancer cell line is due to a constitutively activated extracellular signal-regulated kinase-1-dependent signaling cascade. Oncogene 1997; 14: 2563-73.
79 Aguirre Ghiso JA, Kovalski K. et al. Tumor dormancy induced by downregulation of urokinase receptor in human carcinoma involves integrin and MAPK signaling. J Cell Biol 1999; 147: 89-104.
80 Montuori N, Carriero MV, Salzano S. et al. The cleavage of the urokinase receptor regulates its multiple functions. J Biol Chem 2002; 277: 46932-9.
81 Wilhelm OG, Wilhelm S, Escott GM. et al. Cellular glycosylphosphatidylinositol-specific phospholipase D regulates urokinase receptor shedding and cell surface expression. J Cell Physiol 1999; 180: 225-35.
82 Pyke C, Eriksen J, Solberg H. et al. An alternatively spliced variant of mRNA for the human receptor for urokinase plasminogen activator. FEBS Lett 1993; 326: 69-74.
83 Andreasen PA, Kjøller L, Christensen L. et al. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1-22.
84 Duffy MJ. Urokinase-type plasminogen activator: a potent marker of metastatic potential in human cancers. Biochem Soc Trans 2002; 30: 207-10.
85 Kruger A, Soeltl R, Lutz V. et al. Reduction of breast carcinoma tumor growth and lung colonization by overexpression of the soluble urokinase-type plasminogen activator receptor (CD87). Cancer Gene Ther 2000; 7: 292-9.
86 Lutz V, Reuning U, Kruger A. et al. High level synthesis of recombinant soluble urokinase receptor (CD87) by ovarian cancer cells reduces intraperitoneal tumor growth and spread in nude mice. Biol Chem 2001; 382: 789-98.
87 Jo M, Thomas KS, Wu L. et al. Soluble urokinasetype plasminogen activator receptor inhibits cancer cell growth and invasion by direct urokinase-independent effects on cell signaling. J Biol Chem 2003; 278: 46692-8.